Simian immunodeficiency virus (SIV) was used as a model to study the protective efficacy of an immunization regimen currently being evaluated in humans as candidate vaccines against human immunodeficiency virus. Four macaques (Macaca fascicularis) were immunized with recombinant vaccinia virus expressing the envelope glycoprotein gp160 of SIV/Mne and were subsequently boosted with subunit gp160. Both cell-mediated and humoral immune responses against SIV, including neutralizing antibodies, were elicited. The immunized macaques were shown to be protected from a homologous intravenous virus challenge as determined by serology, lymphocyte co-cultivation, polymerase chain reactions, and in vivo transmission analyses. Since only recombinant immunogens were used and no anti-cellular antibodies were detected in the immunized animals, these results demonstrated that immune responses against viral envelope glycoproteins were sufficient to protect against homologous virus infection in the SIV/macaque model. Cell-free SIV and SIV-infected cell vaccine challenge stocks have been prepared and are being titered in vitro and in vivo. Preliminary data reveal that at the animal infectious dose end-point (as defined by seroconversion) there are still two to three logs of infectious viral particles that can be detected in vitro on certain Epstein-Barr virus-transformed cell lines that are very susceptible to SIV infection. Pig-tailed macaques (Macaca nemestrina) are uniquely sensitive to infection by SIV; this increased susceptibility led us to test whether M. nemestrina peripheral blood lymphocytes (PBLs) could be infected by HIV-1. We have found that these PBLs replicate HIV-1 to high titers. At the University of Washington Primate Center, HIV-1 has been infected intravenously into pig-tailed macaques. The animals seroconverted and became persistently infected. This HIV-1/pig-tailed macaque model needs to be tested with various HIV-1 strains, but may become a valuable animal model for examining the efficacy of vaccine protocols and antiviral therapy.